Yes, Immortality

I wrestled with whether to shoot for a more normal and mundane title, like “In Pursuit of longevity”, but “live a long time!” just doesn’t have the ring that “live forever!” does.

Clarification: I don’t have the Fountain of Youth. I’m relying on the future to do the heavy lifting. Kurzweil’s escape velocity idea is the key idea: we want to live long enough that life expectancy starts increasing more than 1 year per year. Life expectancy is currently stagnant, so we want to live as long as possible to maximize our chances of hitting some sort of transition.

So, the bulk of this post will be devoted to simply living healthily. A lot of the advice is boring and standard: eat your vegetables, exercise, get enough sleep. However, I wanted to check out the science and see what holds up under (admittedly amateur) scrutiny.

(I’ll be ignoring the painfully obvious things, like not smoking. If you’re smoking, stop smoking[1].)

My process: I timeboxed myself to 20 hours of research, ending in August 2017. First, I looked up the common causes of death and free-form generated possible interventions. Then, I followed the citations in the Lifestyle interventions to increase longevity post and then searched Google Scholar, especially for meta-analyses, and read the studies, evaluating them in a non-rigorous way. I discarded interventions that I wasn’t certain about: for example, Sarah lists some promising drugs and gene therapies but based only on animal studies, where I wanted more certainty. I ended up using 30+ hours, so not everything is exhaustively researched as much as I would like: for example, there was a fair amount of abstract skimming. I did not read every paper I reference end-to-end. On the other hand, many papers were also locked behind paywalls so I couldn’t do much more than that.

This means if you read one of these results and implement it without talking to your doctor about it and bad things happen to you, I will ask you: ARE YOU A SPRING LAMB? WHY THE FUCK ARE YOU DOING THINGS A RANDOM PERSON ON THE INTERNET TOLD YOU TO DO? AND WITHOUT VETTING THOSE THINGS?

Or more concretely: you are a unique butterfly, and no one cares except the medical world. What happens for the faceless statistical masses might not happen for you. I will not cover every single possible interaction and caveat, because that is what those huge medical diagnosis books are for, and I don’t have the knowledge to tell you about the contents of those books. Don’t hurt yourself, ask your doctor.

An example: blood donation

First, I wanted to lead with an example of how the wrong methods can cripple a conclusion and end up with bad results.

» For each additional annual blood donation, the all-cause mortality RR (relative risk) is 0.925, with a 95% CI (confidence interval) from 0.906 to 0.943[2]. I’ll be summarizing this information as RR = 0.925[0.906, 0.943] throughout the post.

(Unless otherwise stated, in this post an RR measure will refer to all-cause mortality, and X[Y, Z] CI reports will be values followed by 95% confidence intervals. There will also be references to OR (odds ratio) and HR (hazard ratio)).

There’s even a well fleshed out mechanism, where iron ends up oxidizing parts of the cardiovascular system and damaging it, and hence doing regular blood donation removes excess blood iron.

But there are some possible confounders:

blood donation carries some of the most stringent health screens most people face, which results in a healthy donor effect,

altruism could be correlated with conscientiousness, which might affect health outcomes.

The study cited earlier is observational: they’re looking at existing data gathered in the course of normal donation and studying it to see if there’s an effect. In order to make a blanket recommendation that men should donate blood at some regular interval, what we really want is to isolate the effect of donation by putting people through the normal intake and screening process, and then right before putting the needle in randomize for actually taking the donation or not, or even stick the needle in and not actually draw blood.

No one had done an RCT (randomized controlled trial) in this fashion, and I expect any such study to have a really hard time passing an ethics board when I get numerous calls to help alleviate emergency blood need at a number of times throughout the year.

In other words, there was basically no correlation. In fact, in another section of the paper the authors could get the correlation to come back by slicing their data in a way that better matched the healthy donor process.

The usual hallmarks of science laypeople can pick apart aren’t there: the N is large, there’s a large cross-section of the community (no elderly Hispanic women effect) and there’s no way to even fudge our interpretation of the numbers: we’re not beholden to science’s fetish with p=0.05, so failing the 95% CI could be okay if it were definitely leaning in the right direction. But it’s almost exactly in the middle. The effect isn’t there or is so tiny that it’s not worth considering.

So that’s an example of how things can look like great interventions, and then turn out to have basically no effect. With our skeptic hats firmly in place, let’s dive into the rest!

Easy, Effective

Vitamin D

Vitamin D gets the stamp of approval from both Cochrane and Gwern[4]. Lots of big randomized studies have been done with vitamin D supplementation, so the effect size is pretty pinned down.

You might think that one side of the CI is pretty bad, since RR = 0.98 means the intervention is almost the same as the control. On the other hand, (1) wait until you read the rest of the post (2) keep in mind that it’s very cheap to supplement vitamin D. Your local drugstore probably has a years worth for $20. In a pinch, more sunlight also works, but if you have darker skin, sunlight is less effective.

Unfortunately, “moderate-vigorous” is pretty vague, and the number of multiple comparisons being made is breathtaking.

MET-h is a unit of energy expenditure roughly equivalent to sitting and doing nothing for an hour. Converting different exercises (or intensities of exercise) to MET-h measures can allow directly comparing/aggregating different exercise data. This also makes it easier to decide exactly what “moderate-vigorous” exercise is, roughly mapping to less than 3 MET/h for light, 3-6 for moderate, and above 6 for vigorous.

With this in mind, we can get a regression seeing how additional MET-hs impact RR. From the previous study (2011, N=unknown subset of 844,026):

(While we’re exercising: keep in mind that losing weight isn’t always good: if you’re already at a health weight and start losing weight without intending to, that could be a sign that you’re sick and don’t know it yet (source).)

Unfortunately, most of these studies are based on surveys, which have the usual problems with self reports. There are some studies based on measuring VO2max more rigorously as a proxy for fitness, except those have tiny Ns, in the tens if they’re lucky (it’s expensive to measure VO2max!).

Diet

Overall, many of these studies are observational and based on self-reports; a few are based on randomized provided food, but the economics dictate they have smaller Ns. I’ve put all the diet-related things together, since in aggregate they are fairly impactful (if difficult to put into practice), but note that some of the subheadings contain less certain results.

Like exercise, fruits/vegetables don’t stack forever either; there’s around a 5 serving/day limit after which effects level off. Still, that adds up to around HR = 0.75, competitive with maximally effective exercise.

Potatoes are a notable exception, having a uniquely high glycemic load among vegetables; this roughly means that your blood sugar will spike after eating potatoes, which seems bad. You can find plenty of debate about whether this is in fact bad[6].

Note that the confidence intervals are wide: for example, the red meat CI covers 1.0, which is pretty poor (and yet the best all-cause data I could find). If we were strictly following NHST (null hypothesis significance testing), we’d reject this conclusion. However, I’ll begrudgingly accept waggled eyebrows and “trending towards significance”[8].

If you’re paleo, you might not have cause to worry, since you’re probably eating better than most other red meat eaters, but I have no data for your specific situation.

However, I don’t trust it. Look at how implausibly low that RR is: eating nuts is better than getting the maximum benefit from exercise? How in the world would that work? Unfortunately, I wasn’t able to find any studies that weren’t confounded by religion, so I just have to stay uncertain for now.

Sleep

We spend a third of our lives asleep, of course it matters. The easiest thing to measure about sleep is the length, so plenty of studies have been done on that. You want to hit a Goldilocks zone of sleep length, not too short or not too long. The literature calls this the aptly named U-shape response.

What’s too short, or too long? It’s frustrating, because one study’s “too long” can be another study’s “too short”, and vice versa.

So there’s range right around 8 hours that most studies can agree is good.

You might be fine outside of the Goldilocks zone, but if you haven’t made special efforts to get into the zone, you might want to try and get into that 7-9h zone the studies can generally agree on.

Again, most of these studies are survey based. I can’t find the source, but a possible unique confounder is that sleeping unusually long might be a dependent, not independent variable: if you’re sick but don’t know it, one symptom could manifest as sleeping more.

And, if you get enough sleep but feel groggy, you might want to get checked out for sleep apnea.

However, the study primarily covers the elderly with an average age of 81yo. Sure, one hopes that the effects are universal, but the non-representative population makes it hard to do so. So while flossing looks good, I’m not ready to trust one study, especially when I can’t find a reasonable meta-analysis covering more than a few hundred people.

Note that this is the effect for men: the effect for women is larger. Also, this study directly contradicts the other study, claiming that sitting time has an effect on mortality regardless of activity level. And who in the world sits for less than 3 hours/day during their leisure time? Do they just not have leisure time?

Again, these studies were survey based.

The big unanswered question in my mind is whether exercising vigorously will just wipe the need to not sit. So, I’m not super confident you should get a fancy sit-stand desk.

(However, I do know that writing this post meant so much sitting that my butt started to hurt, so even if it’s not for longevity reasons I’m seriously considering it.)

By itself the RR increments aren’t overwhelming. But since it’s expressed as an increment, if there are 50 increments present in a normal day that we can filter out ourselves, then that adds up to some real impact. The increments aren’t tiny compared to absolute values, though. For example, maximum values in NYC during the 2016 summer:

PM10 ~ 58 μg/m3

CO ~ 1.86 ppm

NO2 ~ 60.1 ppb

O3 ~ 86 ppb

SO2 ~ 7.3 ppb

So the difference between a heavily trafficked metro area and a clean room is maybe twice the percentage impacts we’ve seen, which just doesn’t add up to very much. Beijing is another story, but even then I (baselessly) question the ability of household filtration systems to make a sizable dent in interior air quality.

There are plenty of possible confounders: it seems the way these sorts of studies are run is by looking at city-level pollution and mortality data, and running the regressions on those data points.

That CI width is very concerning; you can cut the data so you get subsets of cardiovascular mortality to become significant, like looking at only non-fatal heart attacks, but it’s not like there’s a breath of correcting for multiple comparisons anywhere, and the study was stopped early due to “likely futility”.

It’s not really an overwhelming result; taking into account the logistical overhead of planning out extra meals in a society based on 3 square meals a day, is it really worth it to lose maybe half a kilogram of fat?

Caloric Restriction

Most longevity folks are really on board the caloric restriction (CR) train. There’s an appealing mechanism where lower metabolic rates produce fewer free radicals to damage cellular machinery, and it’s the exact amount of effort that one might expect from a longevity intervention that actually works.

A common example of CR is the Japanese Ryukyu islands, where there are a surprising number of really old people, who eat a surprisingly low number of calories. However, say it with me: con-found-ed to he-ll! The fact that a single isolated subsection of a single ethnic group have a correlation between CR and longevity doesn’t make me confident that I too can practice CR and tell death to fuck off for a few more years.

Thankfully they’re both randomized, but it doesn’t really help when they end up with conflicting conclusions. You’d hope there would be better support even in animal models for something that should have huge impacts.

What else could we look at? We’re not going to wait for an 80-year human study to finish (the ongoing CALERIE study comes close), so maybe we could look at intermediate markers that are known to have an impact on longevity and go from there.

Pretty good, but that’s also around the impact of green tea. Then, there’s the implied garden of forking paths bringing in multiple comparisons, since the study in the same cluster looks at multiple types of cholesterol and insulin resistance markers.

Finally, there’s the costs: you have to exert plenty of willpower to actually accomplish CR. For something with such large costs, the evidence base just isn’t there.

However, if you’re normotensive then there’s no impact on blood pressure, and only taking into account hypertensives the effect jumps to -4 mmHg. Feel free to keep eating your chocolate, but don’t expect miracles.

You can propose a causal mechanism off the top of your head: people with more friends are less depressed which just has good health outcomes.

However, the alarm bells should be ringing: is the causal relationship backwards? Are healthier people more prone to socializing? Do the confounders never end? The kicker is that all these studies are looking at the elderly (above 50yo at least), which reduces their general applicability even more.

Look, the Ns are tiny, and the studies the meta-analyses are based on are old, and who knows if the Russians were conducting their side of the studies right (Rhodiola originated in Russia, so many of the studies are Russian).

I’m including this because I got excited when I saw it in the original longevity post: stress reduction in a pill! Why do the hard work of meditation when I could just pop some pills (a very American approach, I know)? It just doesn’t look like the evidence base is trustworthy, and my personal experiences confirm that if there’s an effect it’s subtle (Whole Foods carries both Rhodiola and Ashwagandha, so you can try them out for yourself for like $20).

Water Filters

Unfortunately, there’s basically no research on health effects from water filtration in 1st world countries above and beyond municipal water treatment. Most filtration research is either about how adding any filtration to 3rd world countries has massive benefits, or how bacteria can grow on activated carbon granules. Good to know, but on reflection did we expect bacteria to stop growing wherever it damn well pleases?

So keep your Brita filter, but it’s not like we know for sure whether it’s doing anything either. Probably not worth it to go out of your way to get one.

Hand sanitizer

So I keep hand sanitizer in multiple places in my apartment, but does it do anything?

However, keep in mind that home and work are usually less adverse environments than a hospital; there are fewer people with compromised immune systems, there are fewer gaping wounds (hopefully). The cited result is probably an upper bound for us non-hospital folk.

(There’s also this cute study: hand sanitizer contains chemicals that make it easier for other chemicals to penetrate the skin, and freshly printed receipts have plenty of BPA on the paper. This means that sanitizing and then handling a receipt will lead to a spike of BPA in your bloodstream. I presume that relative to eating with filthy hands the BPA impact is negligible, but damn it, researchers are doing these cute small scale studies instead of the huge randomized trials I want.)

Metformin

I didn’t look at metformin in my main study period: I knew it had some interesting results, but it also caused gastrointestinal distress, better known as diarrhea. It brings to mind the old quip: metformin doesn’t make you live longer, it just feels like it[9].

However, while I was reading Tools of Titans, Dominic D’Agostino floated an intriguing idea: he would titrate the metformin dose from some tiny amount until he started exhibiting GI symptoms, and then dialed it back a touch. I don’t think people have started even doing small scale studies around this, but it might be worth looking into.

Other

There’s some stuff that doesn’t have a cost-benefit calculation attached, but I’m including anyways. Or, there are things that won’t help you, but might help the people around you.

CPR

So the odds ratio looks pretty good, except that CI is really wide, and the in absolute terms most people still die from heart attacks: administering CPR raises the chances of survival from 2.5% to 4.3%. So, spending more than a few hours practicing CPR is chasing some really tail risks[10].

However, have two people in your friend group that know CPR, and they can provide a potential buff to everyone around them (two, because you can’t give CPR to yourself). In a similar vein, the Heimlich maneuver might be good to know.

Smoke Alarm testing

Death by fire is not super common. That said, these days it’s cheap to set up a reminder to check your alarm on some long interval, like 6 months.

Quikclot

It’s unlikely you’ll need to do trauma medicine in the field, but if you’re paranoid about tail risk then quikclot (and competitors) can serve as a buttress against bleeding out. Some folks claim that tourniquets are better, but the trauma bandages are a bit more versatile, since you can’t tourniquet your chest.

It’s not magical: since the entire thing becomes a clot, it’s basically just moving a life threatening wound from the field into a hospital. Also make sure to get the bandage form, not the powder; some people have been blinded when the wind blew the clot precursor into their eyes.

Cryonics

Of course, this post wouldn’t be complete without a nod to cryonics. It’s the ultimate backstop. If there all else fails, there’s one last option to make a Hail Mary throw into the future.

Obviously there are no empirical RR values I can give you: you’ll have to estimate your own probabilities and weigh your own values.

WTF, Science?

The overarching story is that we cannot trust anything, because almost all the studies are observational and everything could be confounded to hell by things outside the short list that every study incants they controlled for and we would have no idea.

There is too little disregard for the garden of forking paths in this post-replication crisis world, and many studies are focused on subgroups that plausibly won’t generalize (ex. the elderly).

And what’s up with the heterogeneity in meta-analyses? If every single analysis results in “these results displayed significant heterogeneity”, then what’s the point? What are we doing wrong?

What am I doing?

Maybe you want to know what me myself am doing; I suspect people would be interested for the same reason journalists intersperse a perfectly good technical thriller with human interest vignettes, so here:

Continuing vitamin D supplementation, and getting a couple minutes of sun when I can.

Making an effort to eat more vegetables, less bacon/potatoes (to be honest, I’m more optimistic about cutting out the bacon than potatoes), more fish, and replacing more of my snacking with walnuts.

Keep taking fish oil.

Exercise better: I haven’t upped the intensity of my routine in a while. I probably need some more aerobic work, too.

Tell myself I should iron out my sleep schedule.

Get myself a standing desk for home: I have a standing desk at work, so I’m already halfway there.

Cut back on donating blood. I’ll keep doing it because it’s also wrapped up in “doing good things”, but I was doing it partly selfishly based on the non-quasi-randomized studies. Besides, I have shitty blood.

TLDR

Effective and certain:

Supplement vitamin D.

Effective, possibly confounded:

Exercise vigorously 5 hours/week.

Eat more fruits and vegetables, more fish, less red meat, cut out the bacon.

[1] ↑ If you need me to go through the science of smoking, then let me know and I can do so: I mostly skipped it because I’m already not smoking, and the direction of my study was partly determined by what could be applicable to me. As a non-smoker, I didn’t even notice it was missing until a late editing pass.

[2] ↑ The abstract reports results in terms of percentage mortality decrease, which I believe maps to the same RR I gave.